ABSTRACT Children with obesity are often prescribed drugs without adequate dosing information to account for size and age. Dose adjustments in obese children may be required due to physiologic and body composition changes, as well as alterations in the function of drug eliminating organs, both of which can affect drug disposition. Physiologically-based pharmacokinetic (PBPK) models are mathematical constructs that incorporate physiologic and body composition changes during childhood. By incorporating physiologic and body composition changes with information about the drug's physicochemical properties, PBPK models can be used to predict drug disposition and optimize drug dosing in children with obesity. This proposal will use a systematic approach to developing and evaluating PBPK models in children with obesity, which will provide informed drug dosing in this vulnerable population. We have selected 12 drugs prescribed to children with obesity across the 4 Biopharmaceutical Drug Disposition Classification System (BDDCS) classes, which will allow us to characterize the effect of obesity for drugs that exhibit varying physicochemical and metabolic properties. For these 12 drugs, available pharmacokinetic (PK) data collected from children with obesity will be used to develop PBPK models that incorporate known obesity-induced physiological changes. Then we will develop PBPK models to predict the effect of obesity for 4 additional drugs (one per BDDCS class), and prospectively collect drug concentration data to evaluate these models. The developed models will be used to guide dosing in children with obesity. Once established, this approach will be applied to other commonly used drugs, which will inform dosing of all drugs used in children with obesity or 12.7 million children and adolescents in the U.S.